OVERVIEW: What every practitioner needs to know

Are you sure your patient has a patent ductus arteriosus? What are the typical findings for this disease?

The ductus arteriosus (DA) is a normal and essential fetal structure and is patent at the time of birth. In healthy term infants, the DA closes within 1 to 2 days. The diagnosis of "patent ductus arteriosus (PDA)" implies that the DA remains patent beyond this period of time, and in general refers to a condition in which blood flows from the aorta into the pulmonary artery through a PDA.

The findings typically associated with aorto-pulmonary shunting through the DA are usually not present until the third day following birth and beyond. This delay results from high pulmonary vascular resistance present at birth which gradually falls over time. The appearance of signs and symptoms resulting from a PDA is coincident with this decline in resistance and the accompanying fall in pulmonary arterial pressure. Physical exam signs and symptoms include a systolic heart murmur, "bounding" or palmar pulses, a hyperactive precordium, and a widened pulse pressure (typically >30 mmHg). However, these findings are not sensitive or specific, particularly during the first 2 days after birth.

The diagnostic "gold standard" is an echocardiogram. The echocardiogram can identify anatomic patency of the DA and estimate left-to-right flow. A ductal diameter of greater than 1.5 or 1.6 mm is often considered to be a "moderate" sized PDA. There is less agreement on the best technique for quantitating flow through the DA; options include left atrial/ aortic root diameter ratio, variables describing left heart loading, and subjective assessment of flow characteristics.

What are the risk factors for a patent ductus arteriosus?

Persistent patency of the DA is more common among infants born at early gestational age (particularly <28 weeks gestation) and with extremely low birth weight (<1000 grams) who have respiratory disease, particularly those who require mechanical ventilation. Although a PDA is most commonly diagnosed during the first week of life, the DA may close spontaneously, or after medical therapy, and subsequently re-open. This occurs more commonly among extremely premature infants who develop late-onset sepsis.

What causes the ductus arteriosus to remain patent?

Closure of the DA occurs in two steps. Initially, the DA constricts in response to increased arterial PaO2 and decreased circulating prostaglandins (particularly E2) following birth. Thereafter, hypoxia from ischemia develops in the wall of the DA. The DA then undergoes transformation into a fibrotic ligamentous structure under the influence of a variety of growth factors.

Laboratory studies in animals suggest that this cascade of events is less likely to occur in premature infants because their ductal tissue has lower sensitivity to PaO2 and increased sensitivity to circulating prostaglandin E2. In addition, the wall of the DA in the premature infant is thin compared to the term infant, and ischemia of the vessel wall is therefore less likely because of closer proximity of the vessel wall to the oxygen-carrying blood supply from the adventitia. These factors delay fibrotic changes in the DA in the premature infant and make re-opening of the DA more likely.

What other disease/condition shares some of these symptoms?

Other congenital cardiac lesions might cause some of the signs and symptoms of a PDA. These would include lesions that generate turbulent flow during systole. Examples include lesions that cause regurgitation through an atrio-ventricular valve, stenosis of the aortic or pulmonary valves and aorto-pulmonary connections. Intracardiac shunts through septal defects typically are not confused with a PDA early in life because shunting with turbulent flow through these lesions typically does not occur until after several weeks of age.

Short, soft systolic murmurs beyond the first 2 weeks of life are common in extremely premature infants. These may be caused by a PDA. However, most often they are caused by peripheral pulmonic stenosis (which is of no clinical significance) or a patent foramen ovale. It is important to distinguish between these diagnoses and a PDA because a PDA which persists beyond infancy will need to be followed by an appropriate specialist if does not close (typically a pediatric cardiologist).

What laboratory studies should you request to help confirm the diagnosis?

Brain or B-type natriuretic peptide (BNP) is a protein secreted by the heart muscle in response to excessive stretching of the heart and has been used in adults to diagnose acute decompensated congestive heart failure. Results of investigation of its role in the diagnosis and management of the PDA suggest that it might serve as a biomarker for severity, provide information about the magnitude of effect of the ductal shunt on cardiac function, or predict likelihood of spontaneous closure or closure with echocardiography and medical treatment. More research is needed to establish the sensitivity and specificity of BNP concentrations for diagnosing any feature of the PDA.

Would imaging studies be helpful? If so, which ones?

The most specific and sensitive test for diagnosing a PDA and defining the magnitude of shunt through a PDA is an echocardiogram. In addition to diagnosing the presence of a PDA, an echocardiogram can provide information about: 1) the diameter of the ductus, 2) the direction of shunt, 3) the volume loading of the heart, and 4) effects on aortic blood flow beyond the DA. The disadvantage of this test is that it provides information descriptive of one point in time. Both the diameter of a PDA and the magnitude of the shunt may be quite labile.

A chest radiograph may be helpful in determining whether a PDA has caused cardiomegaly or pulmonary over-circulation.

A recent scheme to classify degrees of severity of a PDA (mild, moderate, severe) using both clinical and echocardiographic criteria has been developed by McNamara et al. Their intent was to create a classification system that would guide treatment or might more clearly define populations enrolled in research studies. To date, this scheme has not been validated.

If you are able to confirm that the patient has a patent ductus arteriosus, what treatment should be initiated?

Following confirmation of the diagnosis of a PDA, there are three strategies of treatment: 1) management of the complications of ductal shunting only, 2) medical treatment to effect closure, and 3) surgical ligation.

Management of Complications of Ductal Shunting:

Some benefit may be derived from strategies that minimize the consequences of ductal shunting. These might be used in situations where definitive therapies are contraindicated or in anticipation of spontaneous closure. In addition, these therapies may be used by clinicians who are not convinced that the potential benefits of therapies to close the PDA outweigh the potential risks of these therapies (see Controversies below).

Decreasing the total blood volume may reduce the effect of pulmonary over-circulation. This is accomplished by reducing total fluid intake with the goal of avoiding over-hydration. This strategy must account for situations in which ductal shunting causes decreased renal blood flow and oliguria. Diuretics may also be administered to reduce the effective blood volume, but their role in the management of PDAs is unclear.

Large ductal shunts may cause hypo-perfusion of the bowel which may increase the likelihood of pathology resulting from bowel ischemia (i.e. small bowel perforation and NEC). If absent or reverse diastolic blood flow is observed on echocardiography in the abdominal aorta, feedings should be either withheld or administered in small volumes with caution.

Medical Treatments to Effect Closure:

The cyclo-oxygenase (COX) inhibitors, indomethacin and ibuprofen, are licensed by the Food and Drug Administration and labeled for the treatment of a PDA. Three strategies for the use of these drugs have been described: 1) prophylactic treatment of infants at risk for persistent ducal patency, 2) treatment of infants with PDAs considered to be hemodynamically significant, and 3) treatment of infants who have echocardiographic evidence of a PDA but lack clinical signs of a significant shunt (asymptomatic PDA).

Prophylactic treatment with indomethacin decreases the likelihood of developing a symptomatic PDA and serious intraventicular hemorrhage (IVH). However, despite these benefits, there is no evidence that mortality or other morbidities are reduced following prophylactic indomethacin, and this therapy does not improve developmental outcome despite decreasing the risk of serious IVH. Treatment of asymptomatic PDAs results in similar outcomes with the exception that this strategy does not reduce the frequency of serious IVH. Although there have been no contemporary randomized, controlled trials investigating the efficacy of indomethacin in the treatment of symptomatic PDAs, older trials suggest that the profile of benefits is similar to that observed when used in the other two strategies.

Ibuprofen appears to be as effective at promoting ductal closure, but like indomethacin does not appear to reduce mortality or any serious morbidity associated with preterm birth. Ibuprofen does not reduce the risk of serious IVH when used prophylactically.

Acetaminophen is emerging as a potential alternative for medical treatment of the PDA. Currently, acetaminophen is not FDA labeled for use in neonates. Trials and observational studies have shown comparable closure rates. Safety and efficacy of acetaminophen for PDA closure, including effect on long-term outcomes, remains to be further systematically quantified.

Surgical Ligation and Cardiac Catheterization:

Surgical closure (ligation) of the DA is usually reserved for infants in whom medical therapies are contraindicated or have failed. Ligation is accompanied by common and serious morbidities. There have been no recent controlled trials of outcomes following ligation. Therefore the risks and benefits of ligation are unknown.

Percutaneous, transcatheter closure of the PDA is an alternative to surgical ligation with potentially fewer adverse effects. Current devices are approved by the US FDA for infants greater than 6 kilos and older than 6 months. However, several case series report successful closure of the PDA in smaller infants, as low as 1190 grams. Safety concerns are greater in smaller and younger infants. To date, large trials comparing surgical ligation to cardiac catheterization are lacking.

What are the adverse effects associated with each treatment option?

The most common adverse effect of both indomethacin and ibuprofen is renal insufficiency manifested by an increase in creatinine and decrease in urine output. This problem is reversible and improves upon discontinuation of the medication. Evidence suggests that ibuprofen is associated with a lower incidence of renal insufficiency compared to indomethacin. Intravenous ibuprofen has been associated with an increase in the incidence of bronchopulmonary dysplasia (BPD). Indomethacin also influences regional blood flow to other organs, most notably the brain and intestines. This may be protective under some circumstances. However, diminished intestinal blood flow may increase the likelihood of bowel perforation and necrotizing enterocolitis. A recent systematic review found decreased risk of necrotizing enterocolitis in infants treated with ibuprofen compared to indomethacin.

Short term complications of PDA ligation include infection, bleeding, and cardiopulmonary deterioration. This latter complication is characterized by myocardial dysfunction and hypotension. Ligation has also been associated with an increased risk of BPD in studies that adjust for confounding factors, such as severity of pre-existing lung disease. It is not clear whether ligation actually increases the risk of BPD or whether the association results from other related factors. Longer term risks of ligation include vocal cord paralysis, an association with neurodevelopmental impairment, and scoliosis. Adults who have undergone PDA ligation as infants often have pulmonary problems such as chronic cough.

A recent meta-analysis, which included mostly cohort studies, found that PDA ligation is associated with decreased mortality and increased neurodevelopmental impairment in survivors. Because of the inherent bias of cohort studies, these findings should be viewed with caution.

What are the possible outcomes of patent ductus arteriosus?

Spontaneous closure:

Describing the "natural history" of a PDA, that is determining rates and timing of spontaneous closure, is challenging because treatment during the early neonatal period is pervasive. However, some information is available from centers in which treatment for PDAs is withheld except in very limited circumstances. Spontaneous closure during the first week of life occurs in approximately 2/3 of infants with birth weights > 1000 grams, and nearly all that remain patent beyond the first week will close prior to discharge. Spontaneous closure during the first week occurs in < 1/3 of infants with a birth weight < 1000 grams. Little can be said about spontaneous rates of closure among these infants thereafter because of the frequency of treatment.

A small or moderate-sized PDA present at the time of discharge will nearly always close during the first year of life. It is not known whether larger PDAs that remain patent beyond the first several weeks of life are likely to close spontaneously.

Outcome of patency of the DA during the neonatal period:

Large left-to-right ductal shunts may impair the mechanical properties of the lung (e.g., decreased dynamic lung compliance), although left-to-right shunting does not impair oxygenation except when associated with severe left ventricular failure. A decrease in lung compliance as a result of shunting may provoke the need to increase ventilatory support in order to maintain adequate ventilation. The possibility of this cascade of events has lead to the hypothesis that the presence of a PDA increases the likelihood of respiratory morbidities such as BPD. This hypothesis is supported by a strong association between the presence of a PDA and BPD. However, treatments to prevent or close PDAs have not been shown to prevent BPD.

Large left-to-right ductal shunts may decrease intestinal blood flow. Bowel ischemia is associated with an increased likelihood of necrotizing enterocolitis (NEC). These associations have lead some to hypothesize that there is a cause and effect relationship between a PDA and NEC. However, as with BPD, prevention or treatment of PDAs does not appear to decrease the likelihood of NEC.

It is not clear whether BPD and NEC are merely associated with the presence of a PDA or represent complications of a PDA.

Long term outcomes of persistent patency of the DA:

Patency of the DA beyond infancy is associated with serious consequences. Exposure of the pulmonary vasculature to increased flow from large left-to-right shunts over a long period of time may cause over-growth of the pulmonary vascular musculature and pulmonary hypertension. This can be an irreversible and fatal complication. For these reasons, infants with PDAs at the time of their initial discharge from the hospital must be followed closely to insure closure, either spontaneous or through some intervention.

What causes this disease and how frequent is it?

Persistent patency of the DA occurs in about 0.03 to 0.08% of term pregnancies, and usually results from a malformation of the DA. It may be accompanied by other malformations of the cardiovascular system. A PDA is more common in Down syndrome and among infants whose mothers have rubella during pregnancy. It is twice as common among females compared to males. Genetic factors may be responsible for PDAs in some term infants. Siblings of term infants with PDAs are at increased likelihood of having a PDA. There are reports of families with individuals with PDAs in multiple generations, suggesting autosomal dominant inheritance.

Persistent patency of the DA is much more common among preterm infants compared to term infants. Reported data on prevalence are variable because of differences among reports in the definition of a PDA, bias due to frequency of acquiring data upon which the diagnosis is based (e.g., echocardiography), the attributes of the cohort in which prevalence is reported, and the postnatal age at which the diagnosis is made. For example, the reported prevalence of a PDA on the third day of life identified by echocardiogram and associated with symptoms among infants with a birth weight < 1000 grams or < 28 weeks ranges from 55 to 70%. At 3-4 days of age, PDAs associated with clinical signs have been reported to occur in about 50% of infants born at 24-27 weeks gestation, 40% at 28-29 weeks gestation and 20% of infants born at 30-31 weeks gestation.

In addition to this powerful effect of maturity on the likelihood of having a PDA, infants on respiratory support are more likely to have a PDA diagnosed. This association does not appear to be related to acquisition bias (i.e. more infants on respiratory are likely to have an echocardiogram performed). Antenatal administration of corticosteroids prior to preterm birth appears to decrease the likelihood of a PDA and increase the responsiveness to treatment with COX inhibitors among infants with PDAs. Among preterm infants, gene polymorphisms (e.g., TFAP2B gene) may act in concert with preterm birth to increase the likelihood of persistent patency of the DA and may account for the variable responsiveness of PDAs to treatment with COX inhibitors.

What complications might you expect from the disease or treatment of the disease?

See the section “What are the possible outcomes of this disease?”

How can a patent ductus arteriosus be prevented?

Treatment with either indomethacin or ibuprofen shortly after birth in premature infants reduces the incidence of a PDA. The likelihood of preventing persistent patency with these medications is inversely related to gestational age. Successful closure following prophylactic treatment ranges from 55-75% among infants with gestational ages of 24-26 weeks to nearly 90% among infants with gestational ages of 29-30 weeks.

(Aggressive: This is a cohort before-after study at a single center. The authors compared prophylactic indomethacin, indomethacin for a symptomatic patent ductus arteriosus, and mandatory ligation for all open ductus arterioses (before) to prophylactic indomethacin, indomethacin for a symptomatic patent ductus arteriosus, and ligation only for "cardiopulmonary compromise" (defined by the attending clinician). There was less necrotizing enterocolitis in the "after" group, with other morbidities about the same.)

(Conservative: This is a cohort before-after study at a single center. The authors compared a conservative approach: little, if ever, use of indomethacin and rarely performing a patent ductus arterious ligation [before] to never using indomethacin and even less use of PDA ligation [after]. Morbidities remained the same in both groups, suggesting that a conservative approach is not harmful.)

(This review article includes a proposed classification scheme that includes both clinical and echocardiographic criteria. The clinical criteria range from C1 [no signs and symptoms] and C4 [severe signs and symptoms] and the echocariographic criteria from E1 [no PDA on echocardiogram] to E4 [large PDA with other signs of volume overload on echocardiogram]. One advantage to the echocardiographic criteria is that the classification uses objective data rather than subjective interpretation.)

(This is a prospective cohort study that examined the use of NT-proBNP in the management of PDA. Early low NT-proBNP values were an independent marker for spontaneous ductal closure in preterm neonates. No threshold of NT-proBNP was able to predict treatment.)

(This is a prospective cohort study that examined the ability of BNP to predict PDA responsiveness to indomethacin. Authors concluded that high baseline BNP levels predict poor response to indomethacin.)

(This is a cohort study that examined the use of troponin T, N-terminal-pro-BNP, and a PDA scoring system on neurodevelopmental impairment. Higher concentrations of the two blood tests and higher scores on the PDA scoring system were associated with worse neurodevelompental outcomes. However, relatively few infants had the outcome of death or severe impairment.)

(This manuscript reports the findings of serial echocardiograms in a cohort of infants with birth weights less than 1000 grams. Spontaneous closure of the DA occurred in more mature infants, those exposed to antenatal corticosteroids and those without the need for ventilatory support. Closure occurred most commonly in the first 8 days after birth, but closure occurred in some infants after this age.)

(This prospective observational study examined the rates of spontaneous closure of the DA at a center in which treatments for the PDA were reserved for very limited circumstances. Among infants with birthweights < 1500, the DA closed spontaneously in 49% by 7 days of age. Among infants > 1000 grams, 94% closed prior to discharge.)

(This is a Cochrane Review of 27 randomized trials of ibuprofen for closure of the PDA. Authors concluded that ibuprofen is as effective as indomethacin for PDA closure. Ibuprofen reduces the risk of NEC and transient renal insufficiency. Further studies are needed to compare long-term outcomes between ibuprofen and indomethacin.)

(This is a Cochrane Review of 7 randomized trials (n=931 infants) comparing ibuprofen with placebo/no intervention. Ibuprofen decreased the incidence of PDA, decreased the need for rescue therapy and the need for surgical ligation. There was no difference in mortality, intraventricular hemorrhage, or chronic lung disease.)

(Analysis examining intravenous indomethacin, ibuprofen, or placebo in preterm infants. The authors found that intravenous ibuprofen was associated with an increased risk of bronchopulmonary dysplasia. There was no improvement in morbidities of prematurity comparing indomethacin or ibuprofen to placebo, other than promotion of ductal closure.)

(This is a Cochrane Review of randomized trials and found 19 trials with 2872 infants that prophylactic indomethacin versus placebo reduced symptomatic patent ductus arterious, ligation, and intraventricular hemorrhage, but no effect on mortality or neurodevelopment.)

(Systematic review of all treatments for the patent ductus arteriosus, including prophylactic, asymptomatic, and symptomatic patent ductus arteriosus approaches. It includes oral and intravenous ibuprofen and indomethacin as well as ligation. After a thorough review, the author concludes there is no evidence that medical or surgical closure of the ductus is beneficial in preterm infants.)

(This is a systematic review of 12 case reports and 2 randomized trials on the use of acetaminophen for treatment of the PDA. More than 76% of PDA responded to treatment with acetaminophen. Treatment response is comparable to ibuprofen and indomethacin.)

(This is a meta-analysis of 39 cohort trials and 1 randomized trial examining outcomes of PDA ligation compared to medical treatment (including non-pharmacologic management). Surgical ligation was associated with increased neurodevelopmental impairment, chronic lung disease, and severe retinopathy of prematurity, but with a reduction in mortality. Authors concluded that PDA ligation is associated with reduced mortality, but with higher neurodevelopmental impairment in survivors. Authors identified at least moderate risk of bias due to lack of controlling for survival bias and pre-ligation confounders.)

(This is a Cochrane Review that included one study (n=154 infants) comparing outcomes between surgical closure and indomethacin treatment. The author found no difference in in-hospital mortality, chronic lung disease, necrotizing enterocolitis, and intra-ventricular hemorrhage. Infants in the surgical group had a higher incidence of retinopathy of prematurity stage III and IV.)

(This is a report of a prospective multi-institutional collaborative including 496 transcatheter PDA closures. Eight percent of patients were < 6 months old; and the smallest patient weighed 2.2 kg. Authors found 11 (2%) high severity adverse events. A younger age was associated with a higher rate of adverse events.)

(This is a retrospective analysis of transcatheter PDA closure in 60 pediatric patients from four cardiology centers. The youngest patient was 0.5 months old and the smallest was 1.19 kg. Twenty-six patients had a weight <6 kg; of these 9 were <3 kg. Closure was achieved in 97% of patients. There were no cases of major complications or death during the follow-up period.)

(This is a cohort study of infants in the US NICHD Neonatal Research Network. Infants who received a patent ductus arteriosus ligation had an increased risk of bronchopulmonary dysplasia and neurodevelopmental impairment.)

(In a secondary analysis of the TIPP trial, the authors found that among infants who survived after PDA ligation, more [53%] had neurosensory impairment versus with those who survived after receiving only medical therapy [34%], which remained significant after multivariate analysis. BPD and severe ROP were also more common after surgical PDA closure. The authors note that there was a large center difference [0-20% incidence of ligation] and that their findings were associations, rather than causation.)

(Single center cohort study that demonstrated that the majority of infants with an open ductus at discharge resolved spontaneously without treatment.)

Ongoing controversies regarding etiology, diagnosis, treatment

Epidemiologic studies confirm an association between the presence of a PDA and serious neonatal morbidities. Although a cause and effect relationship between a PDA and these morbidities has not been established, many clinicians use therapies to prevent or treat PDAs under the assumption that closure decreases the likelihood of these morbidities. For example, in the United States, COX inhibitors are administered to more than 10,000 premature infants annually. An additional smaller number undergo surgical ligation. However, despite nearly three decades of research, the questions of whether these treatments improve outcomes remains unanswered.

There is no doubt that COX inhibitors are effective in closing the PDA. However, the decision to use these drugs should be based on the balance of their risks and benefits, and we have little knowledge about this balance. This lack of knowledge has resulted from limitations of the designs of studies of PDA treatments. Under the assumption that closure of the PDA is beneficial, the purpose of nearly all clinical trials in the modern era has been to determine the most expeditious way in which to achieve this goal. None addressed the more fundamental question of whether closure improves outcome.

To answer this question would require the inclusion of an untreated study group for comparison, a placebo group. Those trials that included a placebo group have permitted treatment of a PDA that persisted after reaching a defined study endpoint, usually within days of enrollment. Thus resulting in high rates of treatment of infants in placebo groups. This consequence has markedly handicapped our ability to answer the critical question of whether closure of the PDA reduces mortality or significant morbidities, and of equal importance has compromised our ability to quantitate adverse consequences of treatments.

Despite these limitations, the message from clinical trials is not encouraging. A recent systematic review by Benitz examined published reports of all treatments to prevent or treat PDAs. He concluded that there was no evidence that any of these therapies improved outcome. These findings do not prove that no infants benefit from treatment. However, these findings have lead some to conclude that routine treatment of a significant proportion of preterm infants cannot be justified. If one adopts the approach that treatment should be reserved for selected infants, the challenge then becomes how to identify individual infants who might benefit from treatment. A validated and practical definition or classification of severity is lacking.

One approach is to reserve treatment only for infants in whom irrefutable evidence of harm is resulting from the PDA. These circumstances might include intractable systemic hypotension or refractory congestive heart failure resulting from large left-to-right ductal shunting. Indomethacin may be the preferred drug under these circumstances because of the association between ibuprofen and increased risk of BPD. Because current data suggests that there is significant morbidity associated with PDA ligation, this treatment should be reserved for very limited circumstances.